DESCRIPTION: (Principal Investigator's) The broad, long-term objectives of thi proposal are: (1) to develop new synthetic methods of use in the design and development of anticancer, antibiotic, and possibly antiviral drugs, and (2) to develop novel methods for the delivery and in vivo activation of anticancer drugs. The facile and controlled introduction of varied substituents about an aromati or heteroaromatic core during structure-activity relationship studies is a recurring problem encountered in the development of many new medicinal agents that are based on small organic molecules. This remains an important factor in drug development even with the advent of combinatorial chemistry, which identifies but does not optimize drug leads. To accomplish this important goal new methods are proposed that are based upon "biominetic" cross-coupling using coenzyme A and coenzyme M mimics. Cyclobutenedione-based synthetic methods have matured to the point that they now are ready for incorporation into challenging, non-methodological problems. Using cyclobutenedione methodology as a seminal component of each system, metallaquinones and porphyrin quinones are being developed as novel anticancer agents.